High purity filtration of media, such as in the fields of biotechnology, chemistry, electronics, pharmaceuticals, and the food and beverage industries requires the use of sophisticated filter modules that are not only capable of a high degree of separation, but that will tend to prevent contamination of the environment, of the medium to be filtered, and of the resulting filtrate. This is designed to prevent unwanted, often dangerous organisms, such as bacteria or viruses, as well as environmental contaminants, such as dust, dirt, and the like from entering into the process stream and end product. To ensure sterility of the filtrate, filter modules must maintain their integrity throughout the filtration process. Accordingly, integrity testing of sterilizing filters is a fundamental requirement of critical process filtration applications in the pharmaceutical industry, and is used to identify filters containing oversized pores or defects that can compromise the retention performance of the filter. FDA guidelines recommend integrity testing of filter modules prior to use and after filtration. Typically this testing is initially performed after steam sterilization to ensure that the filter is not damaged; accordingly, care must be taken to ensure that sterility of the filter, and thus the filtrate, is not compromised. Post-processing, the filter integrity test is performed again in situ to detect whether the filter was compromised during use. This information can be used to alert operators to a potential problem immediately after processing, and to quickly take corrective action. Further, FDA guidelines require that integrity testing documentation be included with batch product records.
There are a variety of methods of integrity testing, including the diffusion test and the pressure hold test. The diffusion test measures the rate of gas transfer through a filter to be tested. At differential gas pressures below the bubble point, gas molecules migrate through water-filled pores of a wetted membrane following Fick's Law of Diffusion. The gas diffusional flow rate for a filter is proportional to the differential pressure and the total surface area of the filter. At a pressure approximately 80% of the minimum bubble point, the gas which diffuses through the filter membrane can be measured to determine a filter's integrity. A diffusional flow reading exceeding a value stated by the manufacturer indicates a variety of problems, including an incorrect temperature, wrong pore size, incompletely wetted membrane, non-integral membrane or seal, or inadequate stabilization time. The pressure hold test, also known as the pressure decay or pressure drop test, is a variation of the diffusion test. In this test, a highly accurate gauge is used to monitor upstream pressure changes due to gas diffusion through the filter. Because there is no need to measure gas flow downstream of the filter, any risk to downstream sterility is eliminated.
These tests require that the filter be wetted, which is a time and water-consuming process. The sensitivity of these tests is also limited in part due to background noise inherent in these tests.
Compared to traditional integrity tests such as gas/liquid diffusion, aerosol integrity testing has a number of advantages including fast test times, and no required wetting of the filter. Aerosol integrity testing has been used in the pharmaceutical industry for detecting defects in HEPA and ULPA grade filters. This test is also used for filters providing sterile gas. However, there are no known applications of aerosol testing to assess the integrity of filters for sterilizing liquids. Aerosol integrity testing has been considered to be unsuitable for liquid filters because particle capture in gases can occur by a number of mechanisms that are not functional in liquids. Mechanisms such as electrostatic attraction and diffusional deposition can result in interception of particles in a filter element, so that penetration of particles through defects is not assured. While aerosol integrity testing has been demonstrated to reliably detect relatively large defects (>100 μm), it has not been previously known how to detect defects on the order of 20 μm or less; i.e., defects that could compromise the retention performance of a liquid sterilizing grade filter. Liquid sterilizing grade filters are defined in the FDA “Aseptic Guideline” (FDA “Guideline on Sterile Drug Products Produced by Aseptic Processing”, Division of Manufacturing and Product Quality, Rockville, Md., June 1987) as those capable of totally retaining a B. diminuta challenge level of 107 cfu/cm2 at a differential pressure of 30 psi.
It therefore would be desirable to provide a methodology for aerosol testing of filters that does not suffer from the drawbacks of the prior art.